Synthesis and antitumor activity of cysteinyl-3,4-dihydroxyphenylalanines and related compounds.
The natural catecholic amino acid 5-S-cysteinyl-3,4-dihydroxyphenylalanine (1) was selectively toxic to a variety of human tumor cell lines in culture and exhibited antitumor activity against L1210 leukemia and B-16 melanoma in mice at doses which were not toxic to the host. Structural analogues of 5-S-cysteinyl-3,4-dihydroxyphenylalanine including several new compounds, were synthesized and tested for growth inhibition of cultured cells of human neuroblastoma YT-nu and Chinese hamster fibroblasts Don-6. Some were also examined for antitumor activity against L1210 and B-16 in vivo. 4-S-Cysteinylcatechols and 2- and 4-S-cyteinylphenols, which cannot be prepared by conventional methods, were synthesized by the reaction of catechols and phenols with cystine and boiling aqueous HBr. 5-S-Cysteinyl- and 2-S-Cysteinyl-3,4-dihyroxyphenylalanine (1 and 2), L-3,4-dihydroxyphenylalanine (L-Dopa), and 2- and 4-S-cysteinylphenol (14 and 15) were toxic to the YT-nu cell line only, while 4-S-cysteinylcatechol (6), 3-S-cysteinyl-5-methylcatechol (8), 5-S-cysteaminyldopamine (9), and 4-methylcatechol were strongly toxic to both cell lines. Compound I (1000 mg/kg), 6 (500 mg/kg), and 8 (400 mg/kg) increased the life span of L1210-bearing mice by 50, 50, and 43%, respectively, and compounds 1 and 8 were marginally effective against B-16 melanoma as well. Compound 9 was too toxic to show any activity. There was a good correlation between the cytotoxicity and the in vivo activity.
D000818:Animals; D000970:Antineoplastic Agents; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003548:Cysteinyldopa / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives*; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009447:Neuroblastoma / Q000188:drug therapy
D000970:Antineoplastic Agents; D003548:Cysteinyldopa; D004295:Dihydroxyphenylalanine